Colon cancer is the second leading cause of cancer related deaths in the United States and other Western countries. Unlike lung cancer, for example, in which smoking has been identified as the prime etiologic factor responsible for the disease, the principle mechanisms underlying colon cancer are complex and incompletely understood. Dietary factors are believed to promote carcinogenesis, especially a high fat intake. Weisburger and Wynder, in Important Advances in Oncology (DeVita et al., eds., Lippincott, Philadelphia, Pa.), pp. 197-221 (1987); and Greenwald and Witkin, in Frontiers of Gastrointestinal Research (Rozen et al., eds., Karger, Basel), pp. 25-37 (1991). At the molecular level, a multi-step process involving a number of mutations is suspected in the progression to colon tumors. Vogelstein et al., N. Engl. J. Med., 319:525-532 (1988); and Fearon and Vogelstein, Cell, 61:759-767 (1990).
Although carcino-embryonic antigen (CEA) is elevated in most advanced colon cancers, it is not an effective indicator of early disease or disease recurrence. Moertel, J. Am. Med. Assoc., 270:943-947 (1993). The currently recommended method of screening for preneoplastic and stage I lesions is sigmoidoscopy with polyp removal and biopsy. Winawer et al., J. Natl. Cancer Inst., 83:243-253 (1991); and Gryska and Cohen, Dis. Colon Rectum, 30:18-20 (1987). This is an invasive technique which incurs considerable discomfort to the patient. The identification of a tumor marker reliably detecting early disease or providing early prognostic information could lead to a diagnostic assay that would greatly aid in the management of this disease.
All eucaryotic cells have a nucleus containing DNA, or chromatin, which is organized by an internal protein scaffolding known as the nuclear matrix (NM). The nuclear matrix was first described in 1974 by Berezney and Coffey. Berezney and Coffey, Biochem. Biophys. Res. Commun., 60:1410-1417 (1974). Penman and Fey disclose a method for selectively extracting insoluble interior nuclear matrix proteins and their associated nucleic acids from cells and determining the particular cell type by analyzing the proteins by two-dimensional gel electrophoresis. U.S. Pat. Nos. 4,882,268, issued Nov. 21, 1989, and 4,885,236, issued Dec. 5, 1989.
The nuclear matrix is believed to be involved in a wide variety of nuclear functions fundamental to the control of gene expression (For a general review see, for example, Fey et al. (1991) Crit. Rev. Euk. Gene Express 1:127-143). Tissue-specific nuclear matrix proteins have been identified in the rat, mouse and human. Fey and Penman, Proc. Natl. Acad. Sci., 8.5:121-125 (1988); Stuurman et al., J. Biol. Chem., 265:5460-5465 (1990); and Getzenberg and Coffey, Mol. Endocrinol., 4:1336-1342 (1990). Changes in the presence or absence of specific nuclear matrix proteins have been associated with cellular transformation and differentiation. Bidwell et al., Proc. Natl. Acad. Sci, 90:3162-3166 (1993); Brancolini and Schneider, Proc. Natl. Acad. Sci., 88:6936-6940 (1991); and Greenfield et al., Proc. Natl. Acad. Sci., 88:11217-11221 (1991). Tumor-specific nuclear matrix proteins have been demonstrated in cancers of human and rat prostates (Partin et al., Cancer Res., 53:744-746 (1993); and Getzenberg et al., Cancer Res., s51:6514-6520 (1991)) and breast (Khanuja et al., Cancer Res., 53:3394-3398 (1993)). Molecular characterization of the specific proteins of the nuclear matrix, however, remains poorly defined, due to the low abundance of these proteins in the cell and their generally insoluble character.
It is an object of this invention to provide colon tumor-associated molecules which are useful as markers for the rapid detection of colon tumors in an individual. It is another object of this invention to provide methods for detecting colon tumors in an individual at early stages of the disease. It is still another object of the invention to provide therapeutic methods and compositions for treating colon cancers in an individual. It is a further object of the invention to provide methods and compositions for monitoring the effect of the therapeutic treatment of colon cancers in an individual. These and other objects and features of the invention will be apparent from the description, figures and claims which follow.